CN113234031B - D-A type aggregation-induced emission compound and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a D-A type aggregation-induced emission compound, a preparation method and application thereof, wherein the compound has a structure shown in a formula (I) or a formula (II), the preparation method of the D-A type aggregation-induced emission compound is simple, the reaction condition is mild, a transition metal catalyst is not needed for catalytic reaction, and the D-A type aggregation-induced emission compound is easier to prepare on a large scale compared with the existing similar compound. The D-A type aggregation-induced emission compound has better cell ester drop targeting property, so the D-A type aggregation-induced emission compound can be applied to lipid drop imaging dyes and liver tissue fat cell imaging dyes.
Description
Technical Field
The invention relates to aggregation-induced emission compounds, in particular to D-A type aggregation-induced emission compounds and a preparation method and application thereof.
Background
Fatty liver has been statistically the second largest liver disease with viral hepatitis only at the second most. Fatty liver is mainly caused by excessive accumulation of fat in fat cells, and the intracellular lactone droplets are important organelles for storing lipid substances. Therefore, the detection of the content of the intracellular lactone drops has important significance for judging the fatty liver. At present, the methods for detecting fatty liver mainly comprise B ultrasonic, nuclear magnetic resonance, blood routine and liver histopathological examination. In contrast, fluorescence detection has the advantages of high sensitivity, real-time in-situ tracking, high resolution and the like, and therefore can be the most direct method for detecting the fatty liver condition.
Aggregation-induced emission (AIE) is a new concept in the field of luminescence proposed in 2001 by Tang-loyal, university of hong Kong science and technology (chem. Commun.2001, 1740-1741). AIE molecules, unlike conventional fluorescent molecules, tend to have a distorted and flexible molecular configuration that makes them susceptible to non-luminescence in the solution state due to non-radiative dissipated excited state energy of intramolecular motion, while luminescence enhancement is achieved in the aggregated state due to restricted opening of radiative transition channels by intramolecular motion. The characteristic that the aggregation-induced emission molecules are brighter and more aggregated completely overcomes the concentration fluorescence quenching effect of the traditional fluorescent molecules, and has immeasurable application prospect in the aspects of biological detection, biological imaging and the like. Currently, imaging of cell membranes, mitochondria, and lysosomes by aggregation-induced emission molecules has been widely reported. While there is little research on ester drop imaging, the development of aggregation-induced emission dyes for ester drop imaging is pressing.
The aggregation-induced emission compound having the structure of the electron donor-acceptor (D-A) has a significant advantage in practical applications. For example, the D-A compound containing a large pi conjugated bridge has a narrow energy band gap and high electron cloud polarization capability, so the D-A compound has huge application prospects in the aspects of near infrared imaging, nonlinear optical imaging, photoacoustic imaging, photothermal therapy and the like; in addition, some aggregation-induced emission molecules of D-a structure have small excited singlet and excited triplet energy level cleavages, which makes it easy to have delayed fluorescence properties, thereby achieving 100% exciton utilization in electroluminescent devices, increasing external quantum efficiency (j.phys.chem.c. 2009,113, 15845-15853), but the reaction conditions are severe to prepare D-a type aggregation-induced emission compounds.
At present, buchwald-Hartwig amination reaction is one of important reactions for synthesizing D-A type aggregation-induced emission compounds. Buchwald-Hartwig amination is a nucleophilic substitution reaction based on the activation of the carbon-halogen bond of an aromatic halide and an amine-based compound, and requires catalysis by a palladium catalyst (Angew. Chem. Int. Ed.1995,34, 1348-1350. In addition, amination reactions based on carbon-oxygen bond activation and carbon-hydrogen bond activation can also be used for synthesis of aggregation-induced luminescent compounds, but still need to be completed under catalysis of transition metal catalysts such as palladium, copper, rhodium, nickel and silver (angew. Chem. Int. Ed.2018,57,11045-11049, chem. Rev.2017,117, 9247-9301). In these reactions, the use of transition metal catalysts is toxic on the one hand and increases the cost of synthesis of the molecule on the other hand. In addition, most amination reactions need to be carried out under inert atmosphere and basic conditions, thereby limiting their large scale production.
Therefore, the development of a D-A type aggregation-induced emission compound with simple synthesis conditions is of great significance.
Disclosure of Invention
The invention provides a D-A type aggregation-induced emission compound for overcoming the defects of complex synthesis and harsh conditions of the existing aggregation-induced emission compound.
Another object of the present invention is to provide a method for preparing the aggregation-inducing luminescent compound of D-A type.
Another object of the present invention is to provide the use of the aggregation-inducing luminescent compound of D-A type.
In order to achieve the purpose, the invention adopts the technical scheme that:
a D-A type aggregation-induced emission compound has a structure shown in a formula (I) or a formula (II):
wherein R is independently selected from
Or one of the foregoing;
r ' and R ' are independently selected from one of hydrogen, phenyl or alkyl, and R ' are not hydrogen at the same time;
R 1 each independently selected from one of hydrogen, halogen, methoxy, methyl, tert-butyl or dimethylamino;
The D-A type aggregation-induced emission compound has a Twisted Intramolecular Charge Transfer (TICT) property because of containing a special electronic structure, so that the D-A type aggregation-induced emission compound emits short and strong fluorescence due to local state transition in a nonpolar medium, and emits obvious red shift and weakened fluorescence due to the TICT effect in a strong polar medium.
In the present invention, the alkyl group means a C1-C20 alkyl group.
More preferably, R 'and R' are each independently selected from H or C1-C10 alkyl.
Preferably, the
Is selected from->
/>
Preferably, the R group is
R 1 Is hydrogen or methoxy.
A preparation method of a D-A type aggregation-induced emission compound comprises the following steps:
will be provided with
Heating the compound and an amine compound in an organic solvent for reaction to obtain a D-A type aggregation-induced emission compound, wherein the reaction system does not contain any transition metal catalyst;
the amine compound has a structure shown in a formula (III) or a formula (IV):
the D-A type aggregation-induced emission compound has a structure shown in a formula (I) or a formula (II):
wherein, formula (I) or
Wherein said R is independently selected from->
One of (1);
r ' and R ' in formula (I) or formula (III) are independently selected from one of hydrogen, phenyl or alkyl, and R ' are not hydrogen at the same time;
R 1 each independently selected from one of hydrogen, halogen, methoxy, methyl, tertiary butyl or dimethylamino;
of formula (II) or (IV)
Is independently selected from>
One kind of (1).
When the amine compound is aromatic amine, n-butyl lithium is preferably added to the system as an activator. The addition of n-butyl lithium can facilitate the activation of aromatic amine and promote the reaction.
Preferably, the organic solvent is one or more of tetrahydrofuran, toluene, dimethyl sulfoxide, and N, N-dimethylformamide.
Preferably, the reaction temperature of the heating is 50 to 150 ℃.
Preferably, the reaction time of the heating is 1 to 40 hours.
The D-A type aggregation-induced emission compound is applied to serving as a lipid drop imaging dye.
The D-A type aggregation-induced emission compound is applied to being used as an imaging dye of liver tissue fat cells.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel D-A type aggregation-induced emission compound, which has better cell ester drop targeting property, so that the D-A type aggregation-induced emission compound can be applied to lipid drop imaging dyes and liver tissue fat cell imaging dyes. The preparation method of the D-A type aggregation-induced emission compound is simple, the reaction condition is mild, an additional transition metal catalyst is not needed for catalytic reaction, and the D-A type aggregation-induced emission compound is easier to prepare on a large scale compared with the existing similar compound.
Drawings
FIG. 1 is a graph showing fluorescence spectra of Compound 1 prepared in example 1 in a mixed solvent of tetrahydrofuran and water at various water ratios;
FIG. 2 is a graph showing fluorescence spectra of Compound 12 prepared in example 12 in a mixed solvent of tetrahydrofuran and water at various water ratios;
FIG. 3 is a graph showing fluorescence spectra of Compound 13 prepared in example 13 in a mixed solvent of tetrahydrofuran/water at various water ratios;
FIG. 4 is a graph showing fluorescence spectra of Compound 14 prepared in example 14 in a mixed solvent of tetrahydrofuran and water at various water ratios;
FIG. 5 is a graph of the cytotoxicity of various concentrations of compounds a) 1, b) 12 and c) 13 evaluated by the MTT method;
FIG. 6 is a graph of the fluorescence spectra of the cellular imaging and imaging signals of compounds a) 1, b) 12 and c) 13;
FIG. 7 co-staining of compounds a) 1, b) 12 and c) 13 with BODIPY495/503 in cells as images;
fig. 8 is an image of compound 12 on mouse fatty liver tissue.
Detailed Description
The invention will be further described with reference to the following specific embodimentsAnd (5) clearing. In the invention, the selected raw materials
The compounds can be purchased directly, or prepared by methods provided by reference references (appl. Phys. Lett.2009,94,253308 acs nano,2020,14, 4265-4275). In the present invention, the amine compound is commercially available. In the present invention, the yield is a separation yield after a chromatographic column separation.
Example 1
Provided is a D-A type aggregation-induced emission compound, which is prepared by the following steps:
adding 100mg of 2, 3-dicyano-5, 6-diphenylpyrazine (0.35 mmol), 1mL of tetrahydrofuran and 1.2 equivalents of piperidine into a 25mL single-mouth bottle, reacting at 70 ℃ for 18h, distilling under reduced pressure after reaction, and purifying by a chromatographic column (eluent is a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 1
The yield is 91.2%, and the nuclear magnetic resonance hydrogen spectrum detection is carried out on the compound 1, and the data are as follows:
1 H NMR(400MHz,CDCl 3 ),δ(ppm):7.52-7.50(d,2H),7.44-7.43(m,2H),7.38-7.28(m,6H),3.90(s,4H),1.78(s,6H). 13 C NMR(400MHz,CDCl 3 ),δ(ppm):154.1,152.0,142.9,137.9,137.5,130.0,129.7,129.3,128.4,128.3,117.9,109.9,48.5,26.0,24.6.HRMS(MALDI-TOF):m/z 340.1675([M] + ),calcd for C 22 H 20 N 4 340.1688).
the reaction equation for the compound is as follows:
the reaction conditions were adjusted without changing the above reactants to form examples 2 to 11, and the influence of the reaction temperature, reaction time and organic solvent on the yield was examined; the selection of the conditions is shown in table 1.
TABLE 1 EXAMPLES 2 to 11
| Organic solvent | Reaction temperature/. Degree.C | Reaction time/h | Yield/% | |
| Example 2 | DMF | 50 | 7 | 91 |
| Example 3 | DMF | 100 | 7 | 85 |
| Example 4 | DMF | 150 | 7 | 83 |
| Example 5 | THF | 70 | 16 | 88 |
| Example 7 | DMSO | 70 | 4 | 95 |
| Example 9 | DMF | 70 | 1 | 20 |
| Example 10 | DMF | 70 | 30 | 89 |
| Example 11 | DMF | 70 | 40 | 89 |
Example 12
Provided is a D-A type aggregation-inducing luminescent compound, which is prepared by the following steps:
100mg of dimethoxy-substituted 2, 3-dicyano-5, 6-diphenylpyrazine (about 0.35 mmol), 1mL of tetrahydrofuran and 1.2 equivalents of piperidine are added into a 25mL single-neck flask, the reaction is carried out at 70 ℃ for 14h, reduced pressure distillation is carried out after the reaction, and the obtained product is purified by a chromatographic column (eluent is a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 1
The yield was 84.2%, and the nmr hydrogen spectroscopy of compound 12 was performed with the following data:
1 H NMR(400MHz,CDCl 3 ),δ(ppm):7.51-7.49(d,2H),7.41-7.39(d,2H),6.86-6.83(m,4H),3.87(s,4H),3.84-3.83(d,6H),1.77(s,6H). 13 C NMR(400MHz,CDCl 3 ),δ(ppm):160.8,159.7,154.0,151.1,142.5,132.5,130.5,130..3,118.1,114.4,113.9,113.7,109.2,55.4,48.5,26..0,24.6.HRMS(MALDI-TOF)::m/z 400.1895([M] + ),calcd for C 24 H 24 N 4 O 2 400.1899).
the reaction equation for the compound is as follows:
example 13
Provided is a D-A type aggregation-induced emission compound, which is prepared by the following steps:
100mg of 2, 3-dicyano-5, 6-diphenylpyrazine (about 0.35 mmol), 1mL of tetrahydrofuran and 1.2 equivalents of pyrrolidine are added into a 25mL single-neck flask, the reaction is carried out at 70 ℃ for 18h, and after the reaction, the reduced pressure distillation is carried out, and the mixture is purified by a chromatographic column (eluent is a mixed solvent of petroleum ether and dichloromethane with the volume ratio of 1
The yield was 93.1%, and the compound 13 was subjected to nmr hydrogen spectroscopy, and the data were as follows:
1 H NMR(400MHz,CDCl 3 ),δ(ppm):7.51-7.49(m.2H),7.41-7.39(m,2H),7.37-7.29(m,6H),3.92-3.89(t,4H),2.10-2.07(m,4H). 13 C NMR(400MHz,CDCl 3 ),δ(ppm):153.1,151.5,141.9,138.1,137.8,130.0,129.6,129.4,128.4,128.3,128.1,118.6,107.8,48.8,25.7.HRMS(MALDI-TOF):m/z 326.1537([M] + ),calcd for C 21 H 18 N 4 326.1531).
the reaction equation for the compound is as follows:
example 14
Provided is a D-A type aggregation-induced emission compound, which is prepared by the following steps:
100mg of 2, 3-dicyano-5, 6-diphenylpyrazine (about 0.35 mmol), 1mL of tetrahydrofuran and 10 equivalents of propylamine were added to a 25mL single-neck flask, and the reaction was carried out at 70 ℃ for 10 hours, followed by vacuum distillation after the reaction and purification by a chromatography column (eluent is a mixed solvent of petroleum ether and dichloromethane at a volume ratio of 1
The yield was 40.4%, and the nmr hydrogen spectroscopy of compound 14 was carried out with the following data:
1 H NMR(400MHz,CDCl 3 ),δ(ppm):7.47-7.45(m,2H),7.37-7.27(m,8H),5.35-5.33(m,1H),3.62-3.57(m,2H),1.79-1.69(m,2H),1.06-1.02(m,3H). 13 C NMR(400MHz,CDCl 3 ),δ(ppm):153.8,153.7,142.3,137.9,137.8,129.9,129.5,129.3,128.3,128.1,128,115.8,110.8,43.1,22.8,11.5.HRMS(MALDI-TOF):m/z315.1597([M+H] + ),calcd for C 20 H 18 N 4 314.1531).
the reaction equation for the compound is as follows:
examples 15 to 23
The preparation process of this example was similar to that of example 1, and in addition, when examples 21 to 23 were prepared, butyl lithium corresponding to 1.1 equivalents of the amine-based compound was added to the reaction system. A series of D-A type aggregation-induced emission compounds are provided, with specific parameters shown in Table 2.
TABLE 2 examples 15 to 23
Application example 1
As seen from FIGS. 1 to 4, compounds 1 and 12 to 14 prepared from example 1 and examples 12 to 14 can be used for fluorescence detection.
Application example 2
From FIG. 5, it can be seen that the toxicity of compound 1 and compounds 12 to 13 at different concentrations to living cells is very small, and the compounds can be used for staining living cells.
Application example 3
After co-incubation of compound 1 and compounds 12-13 with HeLa cells, the green channel signal was collected by confocal microscopy and the collected signal was converted into a spectrum. The degree of overlap with its signal was judged by co-staining with a commercial ester drop dye (BODIPY 495/503).
As can be seen from FIG. 7, compound 1 and compounds 12 to 13 have high overlapping degree with commercial ester drop dyes, very good effect, ester drop targeting property, and can be applied to ester drop imaging.
Application example 4
After the fatty liver tissue of the mouse is soaked in the culture solution containing the compound 12, the fatty liver tissue is washed for a plurality of times by PBS buffer solution and can be directly used for fluorescence imaging.
As can be seen in fig. 8, compound 12 can be used to image the staining of adipocytes.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (7)
1. A D-A type aggregation-induced emission compound is characterized by having a structure shown in the specification
2. A method for producing the D-a type aggregation inducing luminescent compound according to claim 1, comprising the steps of:
will be provided with
Heating the compound and piperidine, pyrrolidine or alanine in an organic solvent to react to obtain a D-A type aggregation-induced emission compound 1, a compound 13 and a compound 14 respectively, wherein the reaction system does not contain any transition metal catalyst;
or will be
And heating the compound and piperidine in an organic solvent for reaction to obtain the D-A type aggregation-induced emission compound 12, wherein the reaction system does not contain any transition metal catalyst.
3. The method for preparing a D-a type aggregation-inducing luminescent compound according to claim 2, wherein the organic solvent is one or more of tetrahydrofuran, 1, 4-dioxane, dimethylsulfoxide, and N, N-dimethylformamide.
4. The method for preparing a D-a type aggregation-inducing luminescent compound according to claim 2, wherein the reaction temperature for heating is 50 to 150 ℃.
5. The method for preparing a D-a type aggregation-inducing luminescent compound according to claim 2, wherein the reaction time for heating is 1 to 40 hours.
6. Use of a D-a type aggregation inducing luminescent compound according to claim 1 for the preparation of a lipid droplet imaging dye.
7. Use of a type D-a aggregation inducing luminescent compound according to claim 1 for preparing a dye for imaging adipose cells of liver tissue.
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